Cognitive decline is one of the most feared consequences of aging among older adults and even minor changes in cognitive function can seriously impact function, ability to live independently, and quality of life. The trajectory of cognitive change with normal aging is influenced by factors including genetics, cognitive reserve, lifestyle, frailty, and comorbid medical conditions. Although there are compelling data suggesting a relationship between cancer, cancer therapy, and cognitive impairment the vast majority of these studies have focused on younger patients (<65 years old) and few studies have focused on 5+ year survivors. However, the majority of cancer survivors are older adults. Furthermore, those who were treated at an older age may be more vulnerable to cognitive decline because factors that influence normal cognitive aging may interact with cancer treatments to increase vulnerability. The objective of this application is to unite the fields of geriatrics, neuropsychology, oncology, and genetics to study the prevalence and trajectory of cognitive impairment in a cohort of older, long-term (5-15 years) survivors of breast cancer and matched healthy controls. Using a prospective, longitudinal study design, we will pursue the following specific aims while controlling for comorbidity and frailty: Aim 1: Examine the association of APOE status, smoking history, and therapeutic exposures on the cognitive performance among older breast cancer survivors compared to controls (age-, race- and education-matched) Aim 2: Utilize Growth Mixture Modeling techniques to determine trajectories of longitudinal change in cognitive function among older breast cancer survivors and controls (age-, race- and education-matched): Aim 3: Explore associations among cognitive reserve, APOE, smoking history and therapeutic exposures on cognitive functioning at study entry and the pattern of longitudinal change. This study is significant because it will fill a major gap in knowledge regarding the factors that increase risk for cognitive decline in older breast cancer survivors. These data are critical in order to weigh the risks and benefits of cancer treatment in the growing aging population. This study is innovative because it will examine the interactions of therapeutic exposures, genetic polymorphisms, and smoking history in predicting differences in cognitive performance between breast cancer survivors and controls controlling for burden of comorbidity and frailty. Furthermore, the longitudinal design will inform whether the trajectory of cognitive change for cancer survivors parallels healthy controls (phase shift hypothesis) or demonstrates a steeper slope (accelerated aging hypothesis). These data will serve as a foundation to identify older breast cancer survivors at risk for cognitive impairment and guide the development of rationale interventions to decrease this risk, with the ultimate goal of preserving the cognitive function and well-being of older survivors of cancer.